title: Simulating cell apoptosis induced sinus node dysfunction.
abstract: Sinus node dysfunction (SND) is correlated to the pacemaker sinoatrial node (SAN) cell apoptosis. This study explores the effect of such a dysfunctional SAN on electrical propagation into neighboring atrial tissue. The Fenton Karma model was extended to simulate mouse SAN and atrial cell action potentials. The cell models were incorporated into a 2D model consisting of a central SAN region surrounded by atrial tissue. The intercellular gap junctional coupling, as quantified by the diffusion constant, was estimated to give conduction speeds as observed in mouse atrial tissue. The size of mouse SAN pacemaking region was estimated using the 2D model. In multiple simulations, the effects of an increasing proportion of apoptotic pacemaker cells on atrial tissue pacing were simulated and quantified. The SAN size that gave a basal mouse atrial cycle length (ACL) of 295 ms was found to be 0.6 mm in radius. At low pacemaker cell apoptosis proportion, there was a drastic increase of ACL. At modest increase in the number of apoptotic cells, bradycardia was observed. The incidence of sinus arrest was also found to be high. When the number of apoptotic cells were 10% of the total number of pacemaking cells, all pacemaking was arrested. Phenomenological models have been developed to study mouse atrial electrophysiology and confirm experimental findings. The results show the significance of cell apoptosis as a major mechanism of SND.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kharche
authors.forename: John
authors.initials: J
authors.lastname: Beling
authors.forename: Irina V
authors.initials: IV
authors.lastname: Biktasheva
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Biktashev
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003198:Computer Simulation; D004562:Electrocardiography; D006325:Heart Atria / Q000503:physiopathology; D051379:Mice; D008955:Models, Cardiovascular; D012804:Sick Sinus Syndrome / Q000503:physiopathology*; D012849:Sinoatrial Node / Q000503:physiopathology*